Various manipulations of the sleep wake cycle have antidepressant effects in endogenously depressed patients. Total sleep deprivation and partial sleep deprivation in the second half of the night induce remissions during the following day. Also, advancing the sleep period several hours earlier than its usual time without a decrease in the length of the sleep period (phase-advance of the sleep wake cycle) also may induce clinical remissions. Some studies show that the timing of various circadian rhythms and REM sleep appears to be shifted to an abnormally early time in depression. In patients with phase-advanced circadian rhythms, both the phase-advance treatment and partial sleep deprivation in the second half of the night, shifts sleep earlier, restoring a more normal relationship between sleep and the other circadian rhythms. If the timing of sleep and not the duration is the critical factor in the sleep deprivation response, then partial sleep deprivation in the first half of the night should not have therapeutic effects. In this study we have examined the relative efficiacy of partial sleep deprivation (PSD) in the first half of the night (E = early) and PSD in the second half of the night (L = late) in a randomized crossover design. All depressed patients underwent baseline sleep, temperature, activity, (24 hour) U.F.C., TRH stimulated TSH response and 24 hour urinary collections for norepinephrine, serotonin and their metabolites in order to investigate the relationship between the sleep deprivation response and the current biochemical and neuroendocrine hypotheses of depression. Of 12 drug free depressed patients (6 UP, 6 BP) six responded to PSD. All six improved on the PSD-L condition. None responded when kept awake in the first half of the night. Results of this study support the hypothesis that the internal phase relationship between sleep and other circadian rhythms is critical to the antidepressant response of PSD. In addition the response to PSD was not restricted to the first night. Improvement was sustained through a second night of PSD and a night of recovery sleep.